Cellular repair factors influencing radiocurability of human malignant tumours

Summary Chinese hamster cells (V79 379A) cells from a human small cell carcinoma of the lung (ME/MAR) and two xenografted human melanomas (HX117 and HX118) have been grown as multicellular spheroids in vitro. The radiation response of these four cell types has been compared when grown as spheroids (200 or 400 pm in diameter) and as single cells from disaggregated spheroids. The radiation sensitivity of tne three human lines irradiated as single cells in air, is similar. In comparison, the V79 cells are more radioresistant. Only the V79 and HX 118 cells show a spheroid size dependent radiation response. The radiation response of spheroids has been assayed using both cell survival and growth delay. V79, ME/MAR and HX 1 17 cells demonstrate a good correlation between the two endpoints whereas with HX 1 18 there appears to be greater cell kill for a given level of growth delay. This may be because HXl 18 is efficient in the repair of potentially lethal damage (PLD). The results support the view that extrinsic factors such as three dimensional contact, hypoxia and repair of PLD can be important and together with the intrinsic cell radiosensitivity will determine the radiation response of tumours.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The radiation response of V79 and human tumour multicellular spheroids – cell survival and growth delay studies

West¹,

Sandhu²,

Stratford³

1984

“…The clinical significance of PLDR, defined here as recovery of survival before subculture, has remained controversial (Twentyman, 1984;Weichselbaum et al, 1982Weichselbaum et al, , 1984 but it seems reasonable that drug combinations which inhibit the ability of tumour cells to repair significant portions of druginduced damage will lead to improved clinical efficacy. The ability of mammalian cells to recover from bleomycininduced damage has been well-documented both in vitro and in vivo (Barranco & Townsend, 1986).…”

Section: Discussionmentioning

confidence: 99%

Platinum-dye complexes inhibit repair of potentially lethal damage following bleomycin treatment

Wang

Herman²,

Ba³

1989

Summary Several new complexes of platinum with positively charged cellular dyes have been synthesised in an effort to find chemotherapeutic drugs with increased antitumour cytotoxicity. As part of this effort, the direct cytotoxicities of some of these complexes as well as their ability to inhibit bleomycin potentially lethal damage repair (PLDR) was studied in vitro in a squamous cancer cell line of human origin . All of the new agents were more cytotoxic against exponentially growing than against plateau phase cell cultures. Exposure of cells to non-lethal drug concentrations for between 1 and 6h led to measurable inhibition of bleomycin PLDR in the case of each drug tested. In order of decreasing ability to inhibit bleomycin PLDR, Pt(fast black)2, Pt(thioflavin)2 and Pt(thionin)2 were more effective than CDDP, while Pt(methylene blue)2, Pt(Rh-123)2 and Pt(pyronin y)2 were less effective. The most directly cytotoxic agents were Pt(thioflavin)2, Pt(pyronin Y)2 and Pt(Rh-123)2 which also proved to be the least selectively toxic drugs towards exponential versus plateau phase cells. These results indicate that several of the new platinum complexes may be effective cytotoxic agents as well as effective inhibitors of DNA repair process following exposure of cells to other DNA interactive modalities.The glycopeptide antibiotic bleomycin has demonstrated clinical usefulness in the treatment of squamous cell cancer of the head and neck (SCCHN) (Turrisi et al., 1978), testicular tumours (Einhorn & Donahue, 1977) and lymphomas (Coltman et al., 1978). It is used in combinations with other agents because bleomycin does not exhibit dose limiting haematopoietic toxicity (Hubbard et al., 1975). When used as a single agent, however, complete response rates are relatively low and the emergence of drug resistance is a common problem (Crooke & Bradner, 1976).To various extents, mammalian tumour cells have the capacity to repair drug-and radiation-induced damage. The ability of cells to recover from potentially lethal damage has been modelled in vitro by maintaining cells in conditions which prevent them from proliferating for various times and thereby allowing time for repair processes to take place (Barranco & Townsend, 1986).Solid tumours and slow growing lymphomas are likely to contain large populations of non-cycling cells, which may have the capacity to repair potentially lethal damage and contribute to regrowth of the tumour. An in vitro system containing cells in stationary phase may be more analogous to the in vivo situation than are cells in exponential growth. Such an experimental model can be created by growing monolayer cell cultures to confluency under conditions of constant medium renewal without subculture. These stationary phase cultures contain a large fraction of non-cycling, but potentially clonogenic, cells (Hahn & Little, 1972). In such model systems, time dependent enhancement of cell survival observed with longer pre-subculture intervals following exposure to cytotoxic agents can be inferred as due to poten...

“…Exceptions have been reported, however ;Weichselbaum et al (1982) described an inherently radioresistant melanoma line and Gerweck et al (1977) and Nilsson et al (1980) reported several radioresistant glioblastoma lines. Unusual repair parameters have been reported in some human tumor cell lines as well.…”

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confidence: 99%

“…This phenomenon has been referred to as recovery from potentially lethal X-ray damage, and may be analogous to liquid-holding recovery in bacteria and yeast (Little, 1969;Hahn & Little, 1972). PLDR has been described in experimental solid and ascites tumours as well as in established human tumour cell lines (Little et al, 1973;Weichselbaum et al, 1982;Guichard et al, in press).…”

mentioning

confidence: 99%

Cellular X-ray repair parameters of early passage squamous cell carcinoma lines derived from patients with known responses to radiotherapy

Weichselbaum¹,

Dahlberg²,

Little³

et al. 1984

Self Cite

Summary We have investigated X-ray survival parameters and repair of potentially lethal damage (PLDR) in ten early passage squamous cell carcinoma cell lines derived from patients who were biopsied before initiation of radiotherapy or after radiation therapy failure.Radiosensitivity (Do) ranged from 1.07 to 1.93 (Gy), extrapolation numbers (fi) from 1.17 to 2.14 and PLD recovery at 24h from 1.4 to 20.3. Despite significant differences in these parameters amongst the cell lines, a firm correlation between radiocurability and any individual radiobiological parameter could not be established. Our data suggest that the mechanisms associated with radioresistance are complex and that any single radiobiological parameter may not predict clinical success or failure.